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Featured researches published by Fang Ding.


Journal of Biological Chemistry | 2010

MicroRNA-10b Promotes Migration and Invasion through KLF4 in Human Esophageal Cancer Cell Lines

Yanyan Tian; Aiping Luo; Yi-Ran Cai; Qin Su; Fang Ding; Hongyan Chen; Zhihua Liu

Recently, microRNAs have emerged as regulators of cancer metastasis through acting on multiple signaling pathways involved in metastasis. In this study, we have analyzed the level of miR-10b and cell motility and invasiveness in several human esophageal squamous cell carcinoma cell lines. Our results reveal a significant correlation of miR-10b level with cell motility and invasiveness. Overexpression of miR-10b in KYSE140 cells increased cell motility and invasiveness, whereas inhibition of miR-10b in EC9706 cells reduced cell invasiveness, although it did not alter cell motility. Additionally, we identified KLF4, a known tumor suppressor gene that has been reported to suppress esophageal cancer cell migration and invasion, as a direct target of miR-10b. Furthermore, overexpression of miR-10b in KYSE140 and KYSE450 cells led to a reduction of endogenous KLF4 protein, whereas silencing of miR-10b in EC9706 cells caused up-regulation of KLF4 protein. Coexpression of miR-10b and KLF4 in KYSE140 cells and coexpression of small interfering RNA for KLF4 mRNA and miR-10b-AS in EC9706 cells partially abrogated the effect of miR-10b on cell migration and invasion. Finally, analyses of the miR-10b level in 40 human esophageal cancer samples and their paired normal adjacent tissues revealed an elevated expression of miR-10b in 95% (38 of 40) of cancer tissues, although no significant correlation of the miR-10b level with clinical metastasis status was observed in these samples.


Journal of Cancer Research and Clinical Oncology | 2004

Differential expression of S100 gene family in human esophageal squamous cell carcinoma

Junfang Ji; Liqun Zhao; Xiuqin Wang; Chuannong Zhou; Fang Ding; Lei Su; Chunlin Zhang; Xuezheng Mao; Min Wu; Zhi-Hua Liu

AbstractPurposeTo study the differential expression of the S100 gene family at the RNA level in human esophageal squamous cell carcinoma (ESCC), and to find the relationship of the S100 gene family with ESCC.MethodsFirstly, the specific primers were designed for the different S100 genes with Software Primer 3, which required that both primer sequences of each S100 gene were from two different exons respectively. Then, the differential expression of 16 S100 genes was examined by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) in 62 cases of ESCC versus the corresponding normal esophageal mucosa. All RT-PCR products were analyzed by 1.5% agarose gel. With Fluor-S MultiImager and Multi-Analyst software, the electrophoresis images were evaluated with statistics analysis using SAS 8.1 software.ResultsEleven out of 16 S100 genes were significantly downregulated (p<0.05) in ESCC versus the normal counterparts such as S100A1, S100A2, S100A4, S100A8, S100A9, S100A10, S100A11, S100A12, S100A14, S100B, and S100P genes. Only the S100A7 gene in the S100 family was markedly upregulated (p<0.05). Moreover, the S100B gene was significantly correlated with histological differentiation of ESCC (p=0.0247), and the deregulation of some S100 genes was closely correlated (p<0.05), such as S100A10/S100A11, S100A2/S100A8, S100A2/S100A14, S100A8/S100A14, and S100A2/S100P etc.ConclusionsThe S100 gene family is closely associated with ESCC.


Clinical Cancer Research | 2006

Stomatin-like Protein 2 Is Overexpressed in Cancer and Involved in Regulating Cell Growth and Cell Adhesion in Human Esophageal Squamous Cell Carcinoma

Liyong Zhang; Fang Ding; Wenfeng Cao; Zhongmin Liu; Wei Liu; Zaicheng Yu; Yu Wu; Wendong Li; Yanda Li; Zhihua Liu

Purpose: Stomatin-like protein 2 (SLP-2) is a novel and unusual stomatin homologue of unknown functions. It has been implicated in interaction with erythrocyte cytoskeleton and presumably other integral membrane proteins, but not directly with the membrane bilayer. We show here the involvement of SLP-2 in human esophageal squamous cell carcinoma (ESCC), lung cancer, laryngeal cancer, and endometrial adenocarcinoma and the effects of SLP-2 on ESCC cells. Experimental Design: Previous work of cDNA microarray in our laboratory revealed that SLP-2 was significantly up-regulated in ESCC. The expression of SLP-2 was further evaluated in human ESCC, lung cancer, laryngeal cancer, and endometrial adenocarcinoma by semiquantitative reverse transcription-PCR, Western blot, and immunohistochemistry. Mutation detection of SLP-2 exons was done by PCR and automated sequencing. Antisense SLP-2 eukaryotic expression plasmids were constructed and transfected into human ESCC cell line KYSE450. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, clonogenecity assay, flow cytometry assay, nude mice tumorigenetic assay, and cell attachment assay were done to investigate the roles of SLP-2 gene. Results: All tumor types we tested showed overexpression of SLP-2 compared with their normal counterparts (P ≤ 0.05). Moreover, immunohistochemistry analysis of mild dysplasia, severe dysplasia, and ESCC showed that overexpression of SLP-2 occurred in premalignant lesions. Mutation analysis indicated that no mutation was found in SLP-2 exons. KYSE450 cells transfected with antisense SLP-2 showed decreased cell growth, proliferation, tumorigenecity, and cell adhesion. Conclusions: SLP-2 was first identified as a novel cancer-related gene overexpressed in human ESCC, lung cancer, laryngeal cancer, and endometrial adenocarcinoma. Decreased cell growth, cell adhesion, and tumorigenesis in the antisense transfectants revealed that SLP-2 may be important in tumorigenesis.


PLOS ONE | 2011

S100A14 Stimulates Cell Proliferation and Induces Cell Apoptosis at Different Concentrations via Receptor for Advanced Glycation End Products (RAGE)

Qinge Jin; Hongyan Chen; Aiping Luo; Fang Ding; Zhihua Liu

S100A14 is an EF-hand containing calcium-binding protein of the S100 protein family that exerts its biological effects on different types of cells. However, exact extracellular roles of S100A14 have not been clarified yet. Here we investigated the effects of S100A14 on esophageal squamous cell carcinoma (ESCC) cell lines. Results demonstrated that low doses of extracellular S100A14 stimulate cell proliferation and promote survival in KYSE180 cells through activating ERK1/2 MAPK and NF-κB signaling pathways. Immunoprecipitation assay showed that S100A14 binds to receptor for advanced glycation end products (RAGE) in KYSE180 cells. Inhibition of RAGE signaling by different approaches including siRNA for RAGE, overexpression of a dominant-negative RAGE construct or a RAGE antagonist peptide (AmphP) significantly blocked S100A14-induced effects, suggesting that S100A14 acts via RAGE ligation. Furthermore, mutation of the N-EF hand of S100A14 (E39A, E45A) virtually reduced 10 µg/ml S100A14-induced cell proliferation and ERK1/2 activation. However, high dose (80 µg/ml) of S100A14 causes apoptosis via the mitochondrial pathway with activation of caspase-3, caspase-9, and poly(ADP-ribose) polymerase. High dose S100A14 induces cell apoptosis is partially in a RAGE-dependent manner. This is the first study to demonstrate that S100A14 binds to RAGE and stimulates RAGE-dependent signaling cascades, promoting cell proliferation or triggering cell apoptosis at different doses.


Cancer Biology & Therapy | 2007

XIAP is highly expressed in esophageal cancer and its downregulation by RNAi sensitizes esophageal carcinoma cell lines to chemotherapeutics

Shuguang Zhang; Fang Ding; Aiping Luo; Anguo Chen; Zaicheng Yu; Shuhua Ren; Zhihua Liu; Lin Zhang

X-linked inhibitor of apoptosis protein (XIAP) is the most potent member of the IAP gene family in terms of its ability to inhibit caspases and suppress apoptosis. In this study, we investigated the expression of XIAP in esophageal cancer tissues and cell lines, and found the elevated expression of XIAP in esophageal cancer tissues compared with normal tissues. Then we used small interfering RNA (siRNA) to block XIAP expression while evaluating the effect of XIAP siRNA on cell apoptosis, and the combined effects with Paclitaxel, Cisplatin, Fluorouracil, and Etoposide in XIAP high expression ESCC cell line KYSE150 and EC9706. The results showed that XIAP siRNA efficiently decreased XIAP expression and induced cell apoptosis. Treatment with XIAP siRNA in combination with Paclitaxel, Cisplatin, Fluorouracil, and Etoposide enhanced chemosensitivity. These results suggest that XIAP might be helpful for diagnosis of ESCC and XIAP siRNA combined with Paclitaxel, Cisplatin, Fluorouracil, and Etoposide may be a feasible strategy to enhance the effects of chemotherapy in patients with ESCC.


Clinical Cancer Research | 2005

Overexpression of Stefin A in Human Esophageal Squamous Cell Carcinoma Cells Inhibits Tumor Cell Growth, Angiogenesis, Invasion, and Metastasis

Wendong Li; Fang Ding; Liyong Zhang; Zhongmin Liu; Yu Wu; Aiping Luo; Min Wu; Ming-Rong Wang; Qimin Zhan; Zhihua Liu

Purpose: Evidence is accumulating that an inverse correlation exists between stefin A level and malignant progression. The aim of this study is to investigate the role of stefin A in human esophageal squamous cell carcinoma cells and to evaluate the possibility of stefin A for cancer therapy. Experimental Design: We stably transfected stefin A cDNA into human EC9706 or KYSE150 esophageal squamous cell carcinoma cells. Subsequently, we evaluated the effect of stefin A overexpression on cell growth, cathepsin B activity, cell motility and invasion, tumor growth, and metastasis. Immunoanalysis was done to assess the expression of factor VIII and to support the localization of stefin A and cathepsin B. We also evaluated the effect of CA074Me, a selective membrane-permeant cathepsin B inhibitor. Results: Both transfection of stefin A and treatment with 10 μmol/L CA074Me significantly reduced cathepsin B activity and inhibited the Matrigel invasion. Combination of both further reduced cathepsin B activity and inhibited the Matrigel invasion. Overexpression of stefin A delayed the in vitro and in vivo growth of cells and significantly inhibited lung metastasis compared with 50% of lung metastasis in xenograft mice from EC9706 or empty vector cells. Transfection with stefin A showed a dramatic reduction of factor VIII staining in the tumors of xenograft mice. Conclusions: Our data strongly indicate that stefin A plays an important role in the growth, angiogenesis, invasion, and metastasis of human esophageal squamous cell carcinoma cells and suggest that stefin A may be useful in cancer therapy.


Biochemical Journal | 2009

A novel p53 target gene, S100A9, induces p53-dependent cellular apoptosis and mediates the p53 apoptosis pathway.

Chunsun Li; Hongyan Chen; Fang Ding; Yu Zhang; Aiping Luo; Ming-Rong Wang; Zhihua Liu

S100A9 (S100 calcium-binding protein A9) is a calcium-binding protein of the S100 family, and its differential expression has been associated with acute and chronic inflammation and several human cancers. Our previous work showed that S100A9 was severely down-regulated in human ESCC (oesophageal squamous cell carcinoma). To further investigate the transcriptional regulation of S100A9, we analysed the S100A9 promoter region and found several putative p53BS (p53-binding sites). Luciferase reporter assays showed that constructs carrying the p53BS exhibited enhanced luciferase activity in response to wild-type p53 activation. Further study demonstrated that S100A9 mRNA and protein expression could be positively regulated in a p53-dependent manner and p53 could bind to p53BS on the S100A9 promoter. Overexpression of S100A9 could induce cellular apoptosis, and this was partly p53-dependent. Knockdown of S100A9 impaired the apoptosis induced by p53. Thus we conclude that a gene down-regulated in ESCC, S100A9, is a novel p53 transcriptional target, induces cellular apoptosis in a partly p53-dependent manner and mediates the p53 apoptosis pathway.


Journal of Biological Chemistry | 2012

Involvement of S100A14 Protein in Cell Invasion by Affecting Expression and Function of Matrix Metalloproteinase (MMP)-2 via p53-dependent Transcriptional Regulation

Hongyan Chen; Yi Yuan; Chunpeng Zhang; Aiping Luo; Fang Ding; Jianlin Ma; Shouhui Yang; Yanyan Tian; Tong Tong; Qimin Zhan; Zhihua Liu

Background: The role of S100A14 in tumorigenesis and the underlying mechanisms have not been fully understood. Results: S100A14 affects cell invasiveness by regulating MMP2 transcription in a p53-dependent manner. Conclusion: S100A14 acts as either an inducer or an inhibitor of cell invasion depending on the p53 status of cells. Significance: These studies significantly increase our understanding of how S100A14 regulates cell invasiveness. S100 proteins have been implicated in tumorigenesis and metastasis. As a member of S100 proteins, the role of S100A14 in carcinogenesis has not been fully understood. Here, we showed that ectopic overexpression of S100A14 promotes motility and invasiveness of esophageal squamous cell carcinoma cells. We investigated the underlying mechanisms and found that the expression of matrix metalloproteinase (MMP)-2 is obviously increased after S100A14 gene overexpression. Inhibition of MMP2 by a specific MMP2 inhibitor at least partly reversed the invasive phenotype of cells overexpressing S100A14. By serendipity, we found that S100A14 could affect p53 transactivity and stability. Thus, we further investigated whether the effect of MMP2 by S100A14 is dependent on p53. A series of biochemical assays showed that S100A14 requires functional p53 to affect MMP2 transcription, and p53 potently transrepresses the expression of MMP2. Finally, RT-quantitative PCR analysis of human breast cancer specimens showed a significant correlation between S100A14 mRNA expression and MMP2 mRNA expression in cases with wild-type p53 but not in cases with mutant p53. Collectively, our data strongly suggest that S100A14 promotes cell motility and invasiveness by regulating the expression and function of MMP2 in a p53-dependent manner.


International Journal of Cancer | 2002

A novel gene, NMES1, downregulated in human esophageal squamous cell carcinoma

Jin Zhou; Huixin Wang; Ailing Lu; Gengxi Hu; Aiping Luo; Fang Ding; Jian Zhang; Xiuqin Wang; Min Wu; Zhihua Liu

To isolate genes with different expression levels in human esophageal SCC, SSH and reverse Northern were performed between cancer tissue and its normal counterpart. Among the differentially expressed genes identified, we report here cDNA corresponding to a 0.88 kb mRNA (NMES1), whose expression was observed in all 36 adjacent normal esophageal mucosae, while 31 (86%) matched cancer tissues showed a marked reduction or complete lack of its expression. Sequence analysis of its full‐length cDNA revealed a gene encoding a predicted polypeptide of 9 kDa. Northern blot showed that NMES1 was distributed mainly in the alimentary tract. The gene was mapped to 15q21.1 by screening the GenBridge 4 RH panel. Immunohistochemistry confirmed the downregulation of NMES1 in esophageal SCC at the protein level and showed that it is a nuclear protein. In situ hybridization revealed its different expression during mouse embryonic development, especially in bone, brain, stomach and intestine. The negative correlation of NMES1 expression with esophageal oncogenesis suggests its suppressive role in tumorigenesis of the esophagus, while the precise function of NMES1 still needs further investigation.


The Journal of Pathology | 2005

Up-regulation of fibronectin in oesophageal squamous cell carcinoma is associated with activation of the Erk pathway

Jian Zhang; Huiying Zhi; Chuannong Zhou; Fang Ding; Aiping Luo; Xun Zhang; Yuntian Sun; Xiuqin Wang; Min Wu; Zhihua Liu

Fibronectin (FN) was found to be up‐regulated in human oesophageal squamous cell carcinoma (ESCC) by cDNA microarray analysis in our laboratory. In order to elucidate the chronology of FN expression at various stages of oesophageal carcinogenesis, RT‐PCR, immunohistochemistry and Western blot analysis were carried out on ESCC tissue samples with different pathological characteristics. FN was mainly localized in the interstitial tissues, and its up‐regulation in ESCC was significantly associated with the depth of invasion by carcinoma (R = 0.803, p < 0.01). To investigate its relationship with the Erk pathway further, pRaf‐1 and pErk‐1/2 expression were also analysed in ESCC. Activation of Erk1/2 and Raf was identified in 63.3% and 60.3% of the tumour specimens, respectively, whereas normal mucosal epithelial tissues were negative. Moreover, a close association was observed between pErk‐1/2 expression and the differentiation grade (R = −0.421, p = 0.002): pErk‐1/2 signal was greater in poorly differentiated tissues than in well and moderately differentiated tissues. Co‐expression of FN and pErk‐1/2 was found at the invasive front of tumour nests by double immunofluorescence staining and there was a statistical correlation between the expression of FN and pErk‐1/2 (p < 0.05). In the cell line EC9706, plasma FN was able to phosphorylate Raf and further activate Erk, but it did not alter MMP‐2 protein expression or activity, indicating that MMP‐2 may not be the downstream target gene of the Erk pathway. All the above data suggest that the up‐regulation of FN contributes to the later stage of oesophageal carcinogenesis, and that activation of the Erk pathway may be involved in the roles of FN in ESCC. Copyright

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Zhihua Liu

Peking Union Medical College

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Aiping Luo

Peking Union Medical College

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Min Wu

Peking Union Medical College

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Hongyan Chen

Peking Union Medical College

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Xiuqin Wang

Peking Union Medical College

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Yi Li

Peking Union Medical College

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Zhi-Hua Liu

Peking Union Medical College

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Chuannong Zhou

Peking Union Medical College

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Jianlin Ma

Peking Union Medical College

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Qimin Zhan

University of Pittsburgh

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